Abstract
BackgroundDiabetic retinopathy (DR) is a leading cause of blindness in working age adults. Approximately 95% of patients with Type 1 diabetes develop some degree of retinopathy within 25 years of diagnosis despite normalization of blood glucose by insulin therapy. The goal of this study was to identify molecular changes in the rodent retina induced by diabetes that are not normalized by insulin replacement and restoration of euglycemia.MethodsThe retina transcriptome (22,523 genes and transcript variants) was examined after three months of streptozotocin-induced diabetes in male Sprague Dawley rats with and without insulin replacement for the later one and a half months of diabetes. Selected gene expression changes were confirmed by qPCR, and also examined in independent control and diabetic rats at a one month time-point.ResultsTranscriptomic alterations in response to diabetes (1376 probes) were clustered according to insulin responsiveness. More than half (57%) of diabetes-induced mRNA changes (789 probes) observed at three months were fully normalized to control levels with insulin therapy, while 37% of probes (514) were only partially normalized. A small set of genes (5%, 65 probes) was significantly dysregulated in the insulin-treated diabetic rats. qPCR confirmation of findings and examination of a one month time point allowed genes to be further categorized as prevented or rescued with insulin therapy. A subset of genes (Ccr5, Jak3, Litaf) was confirmed at the level of protein expression, with protein levels recapitulating changes in mRNA expression.ConclusionsThese results provide the first genome-wide examination of the effects of insulin therapy on retinal gene expression changes with diabetes. While insulin clearly normalizes the majority of genes dysregulated in response to diabetes, a number of genes related to inflammatory processes, microvascular integrity, and neuronal function are still altered in expression in euglycemic diabetic rats. Gene expression changes not rescued or prevented by insulin treatment may be critical to the pathogenesis of diabetic retinopathy, as it occurs in diabetic patients receiving insulin replacement, and are prototypical of metabolic memory.
Highlights
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults
Type 1 diabetes leads to some degree of diabetic retinopathy (DR) in approximately 95% of patients within 20 years of diagnosis [1,2], and the incidence of DR continues to increase due to the dramatic rise in the
As DR occurs in Type I diabetes patients in spite of insulin therapy, this study sought to characterize the limitations of insulin replacement in normalizing diabetes-induced molecular changes in the retina by identifying gene expression alterations resistant to normalization by chronic insulin therapy
Summary
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults. Approximately 95% of patients with Type 1 diabetes develop some degree of retinopathy within 25 years of diagnosis despite normalization of blood glucose by insulin therapy. Interventions and Complications (EDIC), revealed that patients formerly on conventional insulin therapy retained a higher risk for development of complications, including DR, even four [4] and ten [5] years after switching to intensive insulin therapy despite achieving equivalent glycosylated hemoglobin (HbA1c levels) This clinical phenomenon is apparent with Type 2 diabetics as demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS) where a “sustained legacy” of microvascular complication development was evident in the conventional treatment group despite being under intensive treatment recommendations for the past ten years [6]. The clinical and basic research literature clearly supports the hypothesis that some retinal molecular alterations induced during a period of poor or no control cannot be reversed by subsequent good glycemic control and that other molecular alterations are not prevented from developing after initiation of insulin replacement This phenomenon has been termed ‘metabolic memory’ [12].
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